Design,Synthesis And Preliminary Activity Evaluation Of Pazopanib Derivatives

To stimulate angiogenesis needs the help of vascular endothelial growth factor (VEGF).Because vascular endothelial growth factor receptor can be expressed highly,it was chosen to be a very good targeted therapy of cancer drug targets.Pazopanib is a kind of small molecule tyrosine kinase inhibitors that have multiple targets.It can reduce the activity of all sorts of receptor tyrosine kinase.It is an oral VEGF-2 inhibitors and it was Britain’s glaxosmithkline researched and developed.It is approved by the FDA in October 2009.Its indications is advanced renal cell carcinoma.Clinical trials show that most likely side effects of Pazopanib are diarrhea, hair loss and high blood pressure.Its the most serious side effects include cutting-edge reverse type of ventricular tachycardia and arterial thrombosis and so on.So it brings some inconvenience to patients.For patients with advanced renal cell carcinoma,looking for a safe and effective drug has the vital significance.This paper carries on the thorough research for structure-activity relationship of Pazopanib.Based on novelty and innovation of the structure,totally seven new compounds were synthesized by methods of Pazopanib as lead compounds.On the premise of retaining the pyrimidine ring,we get rid of the methyl that has little effect on activity.The methyl connects to the nitrogen atom between the pyrimidine ring with indazole ring.We use bioisosterism,hydrogen bonding interaction theory and principle of split and increase the chlorine atoms in the pyrimidine ring.On the basis of the original structure,We transform the structure of indazole ring and benzene sulfonamide.All the target compounds have not been seen in the literature.They were identified by 1H NMR characterization. The synthetic route has few steps and high yield,and the compounds are easily purified.They can provide reference for the synthesis of compounds of similar structure.We have finished the synthesis of the 20 intermediates and have designed three synthetic routes. And we have finished the synthesis of seven target compounds that have two types.Structure of these compounds have been identified.They are all new structure and they have not been reported by literature.This paper evaluates the target compounds for antitumor activity of human gastric cancer cells.Experiments show that target compounds Ⅰ-1、Ⅰ-2、Ⅰ-3、Ⅰ-4、 Ⅰ-5、Ⅱ-1、Ⅱ-2 have certain anti-tumor activity.Anti-cancer activity of target compound I-1 was higher than Pazopanib.The activity of target compounds Ⅰ-2、 Ⅰ-3、Ⅰ-4、Ⅰ-5 close to Pazopanib. Anti-cancer activity of target compounds Ⅱ-1、 Ⅱ-2 was lower than Pazopanib.This paper analyzes structure-activity relationship of the target compounds:(1)Through hydrogen bonding and enzyme combined with functional groups (pyrimidine ring) is a necessary groups for antitumor activity; (2)On the position of the pyrimidine ring C-5 we introduce halogen, such as: chlorine.This is helpful to enhance the antitumor activity of the compounds; (3)We get rid of the methyl that connects to the nitrogen atom between the pyrimidine ring with indazole ring. has little effect on activity.It almost does not affect the activity; (4)Different inhibitory activity of target compounds shows that in different position of the benzene ring,different substituents were introduced.It makes the activity of compounds have certain difference; (5)We compare target compounds Ⅰ-1-Ⅰ-5 and Ⅱ-1、Ⅱ-2 and find that after the aryloxy replaces the aromatic amino,the activity of the target compounds decrease significantly.The study points out the direction for the design of the target compounds.